Human Breast Milk Contamination with Phthalates and Alterations of Endogenous Reproductive Hormones in Infants Three Months of Age

Phthalates adversely affect the male reproductive system in animals. We investigated whether phthalate monoester contamination of human breast milk had any influence on the postnatal surge of reproductive hormones in newborn boys as a sign of testicular dysgenesis. DESIGN: We obtained biologic samples from a prospective Danish–Finnish cohort study on cryptorchidism from 1997 to 2001. We analyzed individual breast milk samples collected as additive aliquots 1–3 months postnatally (n = 130; 62 cryptorchid/68 healthy boys) for phthalate monoesters [mono-methyl phthalate (mMP), mono-ethyl phthalate (mEP), mono-n-butyl phthalate (mBP), mono-benzyl phthalate (mBzP), mono-2-ethylhexyl phthalate (mEHP), mono-isononyl phthalate (miNP)]. We analyzed serum samples (obtained in 74% of all boys) for gonadotropins, sex-hormone binding globulin (SHBG), testosterone, and inhibin B. RESULTS: All phthalate monoesters were found in breast milk with large variations [medians (minimum–maximum)]: mMP 0.10 (< 0.01–5.53 μg/L), mEP 0.95 (0.07–41.4 μg/L), mBP 9.6 (0.6–10,900 μg/L), mBzP 1.2 (0.2–26 μg/L), mEHP 11 (1.5–1,410 μg/L), miNP 95 (27–469 μg/L). Finnish breast milk had higher concentrations of mBP, mBzP, mEHP, and Danish breast milk had higher values for miNP (p = 0.0001–0.056). No association was found between phthalate monoester levels and cryptorchidism. However, mEP and mBP showed positive correlations with SHBG (r = 0.323, p = 0.002 and r = 0.272, p = 0.01, respectively); mMP, mEP, and mBP with LH:free testosterone ratio (r = 0.21–0.323, p = 0.002–0.044) and miNP with luteinizing hormone (r = 0.243, p = 0.019). mBP was negatively correlated with free testosterone (r = −0.22, p = 0.033). Other phthalate monoesters showed similar but nonsignificant tendencies. CONCLUSIONS: Our data on reproductive hormone profiles and phthalate exposures in newborn boys are in accordance with rodent data and suggest that human Leydig cell development and function may also be vulnerable to perinatal exposure to some phthalates. Our findings are also in line with other recent human data showing incomplete virilization in infant boys exposed to phthalates prenatally

Evaluation of intussusception after oral monovalent rotavirus vaccination in South Africa

BACKGROUND: Postlicensure studies have shown an association between rotavirus vaccination and intussusception. We assessed the risk of intussusception associated with Rotarix (RV1) administration, at 6 and 14 weeks of age, in an upper-middle-income country, South Africa. METHODS: Active prospective surveillance for intussusception was conducted in 8 hospitals from September 2013 through December 2017. Retrospective case enrollment was done at 1 hospital from July 2012 through August 2013. Demographic characteristics, symptom onset, and rotavirus vaccine status were ascertained. Using the self-controlled case-series method, we estimated age-adjusted incidence rate ratios within 1–7, 8–21, and 1–21 days of rotavirus vaccination in children aged 28–275 days at onset of symptoms. In addition, age-matched controls were enrolled for a subset of cases (n = 169), and a secondary analysis was performed. RESULTS: Three hundred forty-six cases were included in the case-series analysis. Post–dose 1, there were zero intussusception cases within 1–7 days, and 5 cases within 8–21 days of vaccination. Post–dose 2, 15 cases occurred within 1–7 days, and 18 cases within 8–21 days of vaccination. There was no increased risk of intussusception 1–7 days after dose 1 (no cases observed) or dose 2 (relative incidence [RI], 1.71 [95% confidence interval {CI} .83–3.01]). Similarly, there was no increased risk 8–21 days after the first (RI, 4.01 [95% CI, .87–10.56]) or second dose (RI, .96 [95% CI, .52–1.60]). Results were similar for the case-control analysis. CONCLUSIONS: The risk of intussusception in the 21 days after the first or second dose of RV1 was not higher than the background risk among South Africa infants.Presented in part: 13th International Rotavirus Symposium, Minsk, Belarus, 29‒31 August 2018.http://cid.oxfordjournals.orgpm2020Paediatrics and Child Healt

Evaluation of Intussusception After Oral Monovalent Rotavirus Vaccination in South Africa

BACKGROUND: Postlicensure studies have shown an association between rotavirus vaccination and intussusception. We assessed the risk of intussusception associated with Rotarix (RV1) administration, at 6 and 14 weeks of age, in an upper-middle-income country, South Africa. METHODS: Active prospective surveillance for intussusception was conducted in 8 hospitals from September 2013 through December 2017. Retrospective case enrollment was done at 1 hospital from July 2012 through August 2013. Demographic characteristics, symptom onset, and rotavirus vaccine status were ascertained. Using the self-controlled case-series method, we estimated age-adjusted incidence rate ratios within 1–7, 8–21, and 1–21 days of rotavirus vaccination in children aged 28–275 days at onset of symptoms. In addition, age-matched controls were enrolled for a subset of cases (n = 169), and a secondary analysis was performed. RESULTS: Three hundred forty-six cases were included in the case-series analysis. Post–dose 1, there were zero intussusception cases within 1–7 days, and 5 cases within 8–21 days of vaccination. Post–dose 2, 15 cases occurred within 1–7 days, and 18 cases within 8–21 days of vaccination. There was no increased risk of intussusception 1–7 days after dose 1 (no cases observed) or dose 2 (relative incidence [RI], 1.71 [95% confidence interval {CI} .83–3.01]). Similarly, there was no increased risk 8–21 days after the first (RI, 4.01 [95% CI, .87–10.56]) or second dose (RI, .96 [95% CI, .52–1.60]). Results were similar for the case-control analysis. CONCLUSIONS: The risk of intussusception in the 21 days after the first or second dose of RV1 was not higher than the background risk among South Africa infants.Presented in part: 13th International Rotavirus Symposium, Minsk, Belarus, 29‒31 August 2018.http://cid.oxfordjournals.orgpm2020Paediatrics and Child Healt

Clinical presentation and management of childhood intussusception in South Africa

PURPOSE: We assessed management and outcomes for intussusception at nine academic hospitals in South Africa. METHODS: Patients≤3 years presenting with intussusception between September 2013 and December 2017 were prospectively enrolled at all sites. Additionally, patients presenting between July 2012 and August 2013 were retrospectively enrolled at one site. Demographics, clinical information, diagnostic modality, reduction methods, surgical intervention and outcomes were reviewed. RESULTS: Four hundred seventy-six patients were enrolled, [54% males, median age 6.5 months (IQR 2.6–32.6)]. Vomiting (92%), bloody stool (91%), abdominal mass (57%), fever (32%) and a rectal mass (29%) represented advanced disease: median symptom duration was 3 days (IQR 1–4). Initial reduction attempts included pneumatic reduction (66%) and upfront surgery (32%). The overall non-surgical reduction rate was 28% and enema perforation rate was 4%. Surgery occurred in 334 (70%), 68 (20%) patients had perforated bowel, bowel resection was required in 61%. Complications included recurrence (2%) and nosocomial sepsis (4%). Length of stay (LOS) was signifcantly longer in patients who developed complications. Six patients died—a mortality rate of 1%. There was a signifcant diference in reduction rates, upfront surgery, bowel resection, LOS and mortality between centres with shorter symptom duration compared longer symptom duration. CONCLUSION: Delayed presentation was common and associated with low success for enema reduction, higher operative rates, higher rates of bowel resection and increased LOS. Improved primary health-care worker education and streamlining referral pathways might facilitate timely management.Bill and Melinda Gates Foundation (BMGF) and Fogarty International Center of the National Institutes of Health.http://link.springer.com/journal/383pm2022Paediatrics and Child Healt

The Feasibility of Formation and Kinetics of NMR Signal Amplification by Reversible Exchange (SABRE) at High Magnetic Field (9.4 T)

¹H NMR signal amplification by reversible exchange (SABRE) was observed for pyridine and pyridine-<i>d</i>₅ at 9.4 T, a field that is orders of magnitude higher than what is typically utilized to achieve the conventional low-field SABRE effect. In addition to emissive peaks for the hydrogen spins at the ortho positions of the pyridine substrate (both free and bound to the metal center), absorptive signals are observed from hyperpolarized orthohydrogen and Ir-complex dihydride. Real-time kinetics studies show that the polarization build-up rates for these three species are in close agreement with their respective ¹H <i>T</i>₁ relaxation rates at 9.4 T. The results suggest that the mechanism of the substrate polarization involves cross-relaxation with hyperpolarized species in a manner similar to the spin-polarization induced nuclear Overhauser effect. Experiments utilizing pyridine-<i>d</i>₅ as the substrate exhibited larger enhancements as well as partial H/D exchange for the hydrogen atom in the ortho position of pyridine and concomitant formation of HD molecules. While the mechanism of polarization enhancement does not explicitly require chemical exchange of hydrogen atoms of parahydrogen and the substrate, the partial chemical modification of the substrate via hydrogen exchange means that SABRE under these conditions cannot rigorously be referred to as a non-hydrogenative parahydrogen induced polarization process

Aqueous NMR Signal Enhancement by Reversible Exchange in a Single Step Using Water-Soluble Catalysts

Two synthetic strategies are investigated for the preparation of water-soluble iridium-based catalysts for NMR signal amplification by reversible exchange (SABRE). In one approach, PEGylation of a variant <i>N</i>-heterocyclic carbene provided a novel catalyst with excellent water solubility. However, while SABRE-active in ethanol solutions, the catalyst lost activity in >50% water. In a second approach, synthesis of a novel di-iridium complex precursor where the cyclooctadiene (COD) rings have been replaced by CODDA (1,2-dihydroxy-3,7-cyclooctadiene) leads to the creation of a catalyst [IrCl­(CODDA)­IMes] that can be dissolved and activated in waterenabling aqueous SABRE in a single step, without need for either an organic cosolvent or solvent removal followed by aqueous reconstitution. The potential utility of the CODDA catalyst for aqueous SABRE is demonstrated with the ∼(−)­32-fold enhancement of ¹H signals of pyridine in water with only 1 atm of parahydrogen

High-Resolution Low-Field Molecular Magnetic Resonance Imaging of Hyperpolarized Liquids

We demonstrate the feasibility of microscale molecular imaging using hyperpolarized proton and carbon-13 MRI contrast media and low-field (47.5 mT) preclinical scale (38 mm i.d.) 2D magnetic resonance imaging (MRI). Hyperpolarized proton images with 94 × 94 μm² spatial resolution and hyperpolarized carbon-13 images with 250 × 250 μm² in-plane spatial resolution were recorded in 4–8 s (largely limited by the electronics response), surpassing the in-plane spatial resolution (i.e., pixel size) achievable with micro-positron emission tomography (PET). These hyperpolarized proton and ¹³C images were recorded using large imaging matrices of up to 256 × 256 pixels and relatively large fields of view of up to 6.4 × 6.4 cm². ¹³C images were recorded using hyperpolarized 1-¹³C-succinate-<i>d</i>₂ (30 mM in water, %<i>P</i>_13C = 25.8 ± 5.1% (when produced) and %<i>P</i>_13C = 14.2 ± 0.7% (when imaged), <i>T</i>₁ = 74 ± 3 s), and proton images were recorded using ¹H hyperpolarized pyridine (100 mM in methanol-<i>d</i>₄, %<i>P</i>_H = 0.1 ± 0.02% (when imaged), <i>T</i>₁ = 11 ± 0.1 s). Both contrast agents were hyperpolarized using parahydrogen (>90% para-fraction) in an automated 5.75 mT parahydrogen induced polarization (PHIP) hyperpolarizer. A magnetized path was demonstrated for successful transportation of a ¹³C hyperpolarized contrast agent (1-¹³C-succinate-<i>d</i>₂, sensitive to fast depolarization when at the Earth’s magnetic field) from the PHIP polarizer to the 47.5 mT low-field MRI. While future polarizing and low-field MRI hardware and imaging sequence developments can further improve the low-field detection sensitivity, the current results demonstrate that microscale molecular imaging <i>in vivo</i> is already feasible at low (<50 mT) fields and potentially at low (∼1 mM) metabolite concentrations